Age-related macular degeneration (AMD) is a leading cause of vision loss in more than 10 million older Americans. For decades, AMD has been characterized by accumulation of extracellular lesions called drusen on the inner surface of Bruch's membrane (BrM), posterior to the retinal pigment epithelium (RPE), in a compartment called the sub-RPE space. Drusen are now recognized as the best known half of a larger system postulated for outer retinal lipid homeostasis that includes highly prevalent extracellular lesions in a compartment called the subretinal space, between the photoreceptors and RPE. Subretinal drusenoid deposits (SDD), which accumulate anterior to the RPE, are thought to clinically manifest as reticular pseudodrusen (RPD). These biomicroscopic signs visible in multiple imaging modalities are highly associated with progression to choroidal neovascularization (CNV) and geographic atrophy (GA), AMD's two late stages. The disparate location of RPD compared to that of classical drusen implies different impact on overlaying photoreceptor cells, different processes leading to late stage AMD, and different biogenesis mechanisms. The effect of RPD on overlying photoreceptors and why RPD are significant risk factors for vision loss remains mysterious. We hypothesize that RPD/SDD, like drusen, are biomicroscopic signs of chorioretinal degeneration that impact the structure and function of photoreceptors at both formative and regressing stages. We predict that RPD/SDD will have more impact on photoreceptors than drusen, because they are in the sub-retinal space and therefore in direct contact with photoreceptors. We further predict that rods will more be affected than cones in both lesions, because the rods are more vulnerable to interruption of their supply route from the choroid than are cones. Thus, we propose to characterize the ultrastructure and natural history of RPD, in relation to the structure and function of overlaying photoreceptors and RPE/choroid health in patients with non- neovascular AMD. Our objectives are two-fold: better understanding of RPD's role in the pathophysiology of AMD, and developing adaptive optics (AO) imaging based biomarkers and biometrics for sensitive and quantitative assessment of photoreceptor degeneration in AMD. We have developed a novel AO imaging instrument that integrates scanning laser ophthalmoscopy and optical coherence tomography (AO-SLO-OCT). This instrument can image the retina with 3-D spatial resolution of 2.5 m X 2.5 m X 5 m thereby allowing for in-vivo ultrastructure assessment of RPD and individual photoreceptors in both en face and cross-sectional planes. We will accomplish our goals by use of AO high resolution imaging and standard multimodal clinical imaging.